GnRH Therapy on Cognition in Down Syndrome
Study Details
Study Description
Brief Summary
Down syndrome (DS) is the most common chromosomal disorder; with the increasing life expectancy, about 80% of DS adults reach age 65 years old. Early Alzheimer's disease (AD) is the most common cause of death within this population. DS individuals already show AD neuropathology by the age of 30, while it becomes clinically recognized in their late forties. DS subjects also exhibit olfaction defects in adulthood.
To date, there is no treatment available for the cognitive or olfactory defects in DS. The development of an effective treatment targeting cognitive dysfunction in DS adolescents/adults would be warranted.
GnRH, a decapeptide secreted by hypothalamic neurons is the pilot light of reproduction in all mammals. Pulsatile GnRH acts on the gonadotrophs via the GnRH receptor (GNRHR) in the pituitary gland to stimulate LH and FSH, which themselves will act on the gonads to produce gametes and steroids. However, GNRHR are also expressed in cerebral cortex, hippocampus, amygdala, habenula, olfactory structures, and adrenal gland, suggesting that GnRH may have a role beyond reproduction.
Recently, GnRH has been shown to be involved in the process of ageing and lifespan control. Notably, in murine models, GnRH acts as an anti-ageing factor, independent of sex hormones. While ageing is characterized by hypothalamic inflammation and diminished neurogenesis, particularly in the hypothalamus and the hippocampus, GnRH was able to promote adult neurogenesis.
The regulation of GnRH secretion is complex and involves hormonal, neuronal input, and environmental factors.
Prévot et al. recently explored cognition within the Ts65Dn model and showed an age-dependent loss of the ability to recognize new objects. Also, these mice exhibit defects in olfaction. Given the role of GnRH in anti-aging mice model, pulsatile GnRH or continuous GnRH infusion (leading to desensitization of the GNRHR) were given to the Ts65Dn mice for two weeks. Amazingly, pulsatile but not continuous GnRH therapy was able to recover cognitive and olfaction defects.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: Pulsatile GnRH pump treatment
|
Drug: GnRH, gonadorelin acetate
Drug administered by a subcutaneous pump during 24 weeks, at a dosage of 75 ng/kg/pulse giving a pulse every 90 minutes in women and every 120 minutes in men.
Other Names:
|
| Placebo Comparator: Pulsatile placebo pump treatment
|
Drug: 0.9% NaCl
Drug administered by a subcutaneous pump during 24 weeks, at a dosage of 75 ng/kg/pulse giving a pulse every 90 minutes in women and every 120 minutes in men.
|
Outcome Measures
Primary Outcome Measures
- Cognition [Baseline to end of treatment (Week 24)]
Montreal Cognitive Assessment (MoCA) total score ranges between 0 and 30 (cut-off set at 26 for the healthy population) Higher scores reflect better performance.
Secondary Outcome Measures
- Olfaction [baseline to Week 12, and to the end of treatment (Week 24)]
The "Sniffin' Sticks" test is a widely used tool for assessment of olfactory performance consisting of three subtests: olfactory threshold (T), odor discrimination (D) and odor identification (I). Each subtest may be scored 1-16. The sum of the three score, the TDI, gives a score 3-48. Higher scores reflect better performance. Most recent normative data is on an sample of more than 9000 subjects. European Archives of Oto-Rhino-Laryngology (2019) 276:719-728 doi.org/10.1007/s00405-018-5248-1
- Amyloidosis [baseline to Week 12, and to the end of treatment (Week 24)]
change in amyloidosis biomarkers (Aβ1-40, Aβ1-42, and truncated forms)
- Brain MRI [baseline to the end of treatment (Week 24)]
change in brain MRI signals
- Health-related quality of life (HRQoL) [baseline to Week 4, 12, and to the end of treatment (Week 24)]
The health-related quality of life (HRQoL) can be used to measure the effects of healthcare interventions and provide quality-improvement outcomes. The Short Form-12 (SF-12) Health Survey is widely used in measuring HRQoL. SF-12 is a reliable, valid measure in a variety of population groups; it is an equivalent substitute for the SF-36v2 for the summary scales. The response to each of the 12 items is weighted separately by the physical and mental component summary (PCS and MCS) regression coefficients and then calculated to give the SF-12 PCS and MCS scores. A booklet "SF-12: How to score the SF-12 Physicial and Mental Health Summary Scales" by Ware, Kosinski and Keller contains the algorithm to be used for the scoring of the PCS and MCS components.
Other Outcome Measures
- Glycemia [baseline to Week 12, and to the end of treatment (Week 24)]
Glucose concentration (mmol/L) is a metabolic parameter.
- Insulinemia [baseline to Week12, and to the end of treatment (Week 24)]
Insulin concentration (nmol/L) is a metabolic parameter.
- Leptinemia [baseline to Week 12, and to the end of treatment (Week 24)]
Leptin concentration (µg/L) is a metabolic parameter.
- Glycated hemoglobin (HbA1c) [baseline to Week 24]
Glycated hemoglobin (mmol/mol and %) is a metabolic parameter.
- Interleukin-6 (IL-6) [baseline to Week 24]
IL-6 (pg/mL) is an inflammatory mediator.
- Interferon-alfa (IFN-a) [baseline to Week 24]
IFN-a (pg/mL) is an inflammatory mediator.
- Tumor necrosis factor- alfa (TNF-a) [baseline to Week 24]
TNF-a (pg/mL) is an inflammatory mediator.
- Total cholesterol [baseline to Week 24]
Total cholesterol (mmol/L) is a metabolic parameter.
- High density lipoprotein (HDL)-cholesterol [baseline to Week 24]
HDL-cholesterol (mmol/L) is a metabolic parameter.
- Low density lipoprotein (LDL)-cholesterol [baseline to Week 24]
LDL-cholesterol (mmol/L) is a metabolic parameter.
- Triglycerides [baseline to Week 24]
Triglycerides (mmol/L) is a metabolic parameter.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Diagnosis of trisomy 21
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Ability to follow the procedures of the study
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Olfactory impairment (Sniffin' Sticks, identification score: for men ≤11, for women ≤12)
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Consent to a non-hormonal contraception during the whole duration of the study
Exclusion Criteria:
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Clinical or biochemical findings suggesting acute illness/hospitalization
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Chronic alcohol abuse, illicit drug use, or anabolic steroid abuse
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Pituitary adenoma and other hormone-dependent tumours
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Participation in another clinical study
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Intention to become a parent during the course of the study
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Pregnant or breastfeeding women
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Participant or his/her legal representative do not want to be informed in case of incidental findings
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Hôpitaux Universitaires de Genève (HUG) | Geneva | GE | Switzerland | 1205 |
| 2 | Centre Hospitalier Universitaire Vaudois (CHUV) | Lausanne | Vaud | Switzerland | 1011 |
Sponsors and Collaborators
- Nelly Pitteloud
Investigators
- Principal Investigator: Nelly Pitteloud, MD, Endocrinology, Metabolism, Diabetology (CHUV)
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- Lutre-UP
- 2020 DR 2112
- 2020-00270